E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Glomerulosclerosis |
Glomerulosclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Glomerulosclerosis |
Glomerulosclerosis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Injuries, poisonings, and occupational diseases [C21] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067757 |
E.1.2 | Term | Focal segmental glomerulosclerosis |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objectives of this study are to investigate safety, tolerability, and the pharmacokinetic and pharmacodynamic profile of BI 764198 vs. placebo administered orally once daily for 12 weeks in patients with primary FSGS or with TRPC6 mutations causing FSGS. |
Los objetivos principales de este estudio son investigar la seguridad, la tolerabilidad y el perfil farmacocinético y farmacodinámico de BI 764198 frente a placebo administrado por vía oral una vez al día durante 12 semanas en pacientes con GEFS primaria o con mutaciones en TRPC6 que causan GEFS. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male and female patients 18 years to 75 years (both inclusive) of age on the day of signing informed consent. - Patients diagnosed with biopsy proven primary FSGS or documented TRPC6 gene mutation causing FSGS prior to screening visit. - Average UPCR ≥ 1500 mg/g based on two 24 hour urine samples collected at least 7 days apart at screening. - Completion of initial corticosteroid therapy course (if applicable) or discontinuation due to intolerance before entry to the trial. - If applicable, corticosteroid therapy (i.e. prednisone) of ≤15 mg/day or ≤30 mg on alternate days with stable dose for at least 2 weeks at randomization, with no plan to change the dose during the study. - Patients treated with ACE inhibitors, ARBs, finerenone, aldosterone inhibitors, or SGLT2 inhibitors should be on a stable dose for at least 4 weeks prior to screening visit with no plan to change the dose during the study. - Body Mass Index (BMI) of ≤ 40 kg/m2 at screening visit. - Women of childbearing potential (WOCBP) must be willing and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the informed consent form (ICF). Men must be willing and able to use condom if their partner is a WOCBP. |
- Pacientes de ambos sexos, de entre 18 y 75 años (ambos inclusive) el día de la firma del consentimiento informado. - Pacientes con diagnóstico de GEFS primaria confirmada por biopsia o mutación en el gen TRPC6 documentada que causa GEFS, antes de la visita de selección. - Promedio de CPCO≥ 1500 mg/g basado en dos muestras de orina de 24 horas recogidas con al menos 7 días de diferencia en la selección. - Finalización de la tanda inicial del tratamiento con corticosteroides (si corresponde) o suspensión del tratamiento debido a intolerancia antes de entrar en el ensayo. - Si corresponde, tratamiento con corticosteroides (es decir, prednisona) de ≤15 mg/día o ≤30 mg en días alternos con una dosis estable durante al menos 2 semanas al azar, sin intención de modificar la dosis durante el estudio. - Los pacientes tratados con inhibidores de la ECA, ARAs, finerenona, inhibidores de la aldosterona o inhibidores de SGLT2 deben recibir una dosis estable durante al menos 4 semanas antes de la visita de selección, sin intención de modificar la dosis durante el estudio. - Índice de Masa Corporal (IMC) ≤ 40 kg/m2 en la visita de selección. - Las mujeres con posibilidad de quedarse embarazadas (WOCBP) deben estar dispuestas y ser capaces de utilizar métodos anticonceptivos altamente eficaces según la directriz ICH M3 (R2); es decir, aquellos con una tasa de ineficacia baja, inferior al 1% al año, cuando se utilicen correctamente y de forma sistemática. En el formulario de consentimiento informado (CI) se proporciona una lista de métodos anticonceptivos que cumplen estos criterios. Los hombres deben estar dispuestos a usar preservativo y ser capaces de hacerlo si su pareja es una mujer con posibilidad de quedarse embarazada (WOCBP). |
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E.4 | Principal exclusion criteria |
- Known monogenic (with the exception of TRPC6 gene mutations) or clinical or histologic evidence of secondary FSGS. - Documented Alport syndrome, Nail Patella syndrome, diabetic nephropathy, IgA nephropathy, lupus nephritis, or monoclonal gammopathy (e.g., multiple myeloma). - Concomitant use of calcineurin inhibitors. - Concomitant treatment with cytotoxic agents (cyclophosphamide, chlorambucil), or CD20 monoclonal antibody, e.g., rituximab, within 5 half-lives before screening visit. Note: use of other immunosuppression therapies considered as standard of care may be allowed as long as the patient remains on stable therapeutic dose throughout the study. - Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (CKD EPI formula based on serum creatinine and cystatin C) at screening visit. - Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >3X the upper limit of normal (ULN) at screening visit. - QTc intervals (QTcF) greater than 450 ms in males or greater than 470 ms in females, or any other clinically relevant ECG findings (at the investigator’s discretion) at screening visit. - Detection of graded cataract by LOCS III higher than NC1/NO1, C0, P0 in the slit lamp eye examination at screening visit. Planned cataract surgery during participation in the study. Patients with cataract who have undergone lens replacement are not excluded. - Women who are pregnant, nursing, or who plan to become pregnant while in the study.
Further criteria apply. |
- Signos histológicos, clínicos o monogénicos (con excepción de la mutación en el gen TRPC6) conocidos de GEFS secundaria. - Síndrome de Alport, síndrome onicorrotuliano, nefropatía diabética, nefropatía por IgA, nefritis lúpica o gammapatía monoclonal (p.ej. mieloma múltiple) documentados. - Uso concomitante de inhibidores de la calcineurina. - Tratamiento concomitante con fármacos citotóxicos (ciclofosfamida, clorambucil), o con anticuerpos monoclonales anti-CD20 (p. ej., rituximab) dentro de las 5 semividas, antes de la visita de selección. Nota: Se puede permitir el uso de otros tratamientos de inmunosupresión considerados de referencia siempre que el paciente permanezca con una dosis terapéutica estable durante todo el estudio. - Tasa estimada de filtración glomerular (TFGe) < 30 mL/min/1,73 m2 (fórmula EPI de la ERC basada en la creatinina sérica y la cistatina C) en la visita de selección. - Alanina aminotransferasa (ALT)/aspartato aminotransferasa (AST) > 3 veces el límite superior de la normalidad (LSN) en la visita de selección. - Intervalos QTc (QTcF) superiores a 450 ms en varones o superiores a 470 ms en mujeres, o cualquier otro hallazgo clínicamente relevante del ECG (a discreción del investigador) en la visita de control. - Detección de cataratas graduadas por LOCS III superiores a NC1/NO1, C0, P0 en el examen ocular de la lámpara de hendidura en la visita de control. Cirugía de cataratas planificada durante la participación en el estudio. No se excluyen los pacientes con catarata que se hayan sometido a un reemplazo de lentes. - Mujeres embarazadas, lactantes o que planean quedarse embarazadas durante el estudio.
Se aplican otros criterios. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1) Patients achieving at least 25% reduction in 24-hour urine proteincreatinine ratio (UPCR) relative to baseline (visit 3) at week 12. |
1) Pacientes que alcancen una reducción de al menos un 25% en el cociente de proteína/creatinina en orina (CPCO) de 24 horas respecto al valor inicial (visita 3) en la semana 12. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) 12 weeks |
1) 12 semanas |
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E.5.2 | Secondary end point(s) |
1) Change in UPCR relative to baseline (visit 3) at weeks 4, 8, and 12 2) Change in UPCR relative to screening at week 13 3) Change in 24-hour urinary protein excretion relative to screening at week 12 4) The following pharmacokinetic parameters of BI 764198 will be determined if feasible: - Steady state trough concentration Cpre,ss on week 4 and week 12 |
1) Cambio en el CPCO respecto al valor inicial (visita 3) en las semanas 4, 8 y 12 2) Cambio en el CPCO en relación con la selección en la semana 13 3) Cambio en la excreción de proteínas en orina de 24 horas en relación con la selección en la semana 12 4) Si es posible, se determinarán los siguientes parámetros farmacocinéticos del BI 764198: - Concentración mínima en estado estacionario Cpre,ee en la semana 4 y en la semana 12 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) weeks 4,8, and 12 2) week 13 3) week 12 4) weeks 4 and 12 |
1) semanas 4, 8 y 12 2) semana 13 3) semana 12 4) semanas 4 y 12 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
United States |
Belgium |
France |
Germany |
Hungary |
Ireland |
Italy |
United Kingdom |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS |
Última visita del último paciente |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 24 |